chr4-155777525-T-A

Variant names:

• chr4-155777525-T-A
• rs200168603
• NM_000857.5:c.180T>A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000857.5(GUCY1B1):​c.180T>A​(p.Asn60Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000974 in 1,523,966 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00078 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0010 (1 hom.)
• Consequence: GUCY1B1 NM_000857.5 missense, splice_region
• Scores: Splicing: ADA: 0.0008829
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.949

Genes affected

GUCY1B1 (HGNC:4687): (guanylate cyclase 1 soluble subunit beta 1) This gene encodes the beta subunit of the soluble guanylate cyclase (sGC), which catalyzes the conversion of GTP (guanosine triphosphate) to cGMP (cyclic guanosine monophosphate). The encoded protein contains an HNOX domain, which serves as a receptor for ligands such as nitric oxide, oxygen and nitrovasodilator drugs. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2014]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02180481).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GUCY1B1	NM_000857.5	c.180T>A	p.Asn60Lys	missense_variant, splice_region_variant	Exon 4 of 14	ENST00000264424.13	NP_000848.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GUCY1B1	ENST00000264424.13	c.180T>A	p.Asn60Lys	missense_variant, splice_region_variant	Exon 4 of 14	1	NM_000857.5	ENSP00000264424.8

Frequencies

GnomAD3 genomes AF: 0.000782 AC: 119 AN: 152196 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00148

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000836 AC: 208 AN: 248902 Hom.: 1 AF XY: 0.000874 AC XY: 118 AN XY: 135036

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.000755

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.000279

Gnomad NFE exome AF: 0.00146

Gnomad OTH exome AF: 0.000994

GnomAD4 exome AF: 0.000995 AC: 1365 AN: 1371652 Hom.: 1 Cov.: 24 AF XY: 0.00102 AC XY: 702 AN XY: 687786

Gnomad4 AFR exome AF: 0.0000315

Gnomad4 AMR exome AF: 0.000718

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000593

Gnomad4 FIN exome AF: 0.000319

Gnomad4 NFE exome AF: 0.00123

Gnomad4 OTH exome AF: 0.000664

GnomAD4 genome AF: 0.000781 AC: 119 AN: 152314 Hom.: 1 Cov.: 33 AF XY: 0.000752 AC XY: 56 AN XY: 74494

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00149

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.00127 Hom.: 0

Bravo AF: 0.000790

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00123 AC: 10

ExAC AF: 0.000927 AC: 112

EpiCase AF: 0.00191

EpiControl AF: 0.00172

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.180T>A (p.N60K) alteration is located in exon 4 (coding exon 4) of the GUCY1B3 gene. This alteration results from a T to A substitution at nucleotide position 180, causing the asparagine (N) at amino acid position 60 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	19
DANN	Benign	0.95
DEOGEN2	Benign	0.20	.;.;T;.
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.27
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.88	D;D;D;D
M_CAP	Benign	0.0066	T
MetaRNN	Benign	0.022	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.29	.;.;N;N
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.8	N;N;N;N
REVEL	Benign	0.11
Sift	Benign	0.22	T;T;T;T
Sift4G	Benign	0.44	T;T;T;T
Polyphen		0.0	B;.;B;B
Vest4		0.17
MutPred		0.61		Gain of ubiquitination at N60 (P = 0.0351);.;Gain of ubiquitination at N60 (P = 0.0351);Gain of ubiquitination at N60 (P = 0.0351);
MVP		0.56
MPC		1.4
ClinPred		0.017	T
GERP RS		3.0
Varity_R		0.28
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00088
dbscSNV1_RF	Benign	0.084
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs200168603; hg19: chr4-156698677; COSMIC: COSV52377037;